Vasculitis refers to a heterogeneous group of disorders leading to inflammatory destruction of blood vessels. Both, arteries and veins may be affected. Classification of vasculitis can take place by indicating the underlying cause, the location of the affected vessels or the type or size of the blood vessels predominantly attacked. Usually, there is an immune component, but the triggering incident is often unknown. In cases autoantibodies are found said autoantibodies are sometimes used for disease classification, as in ANCA (anti neutrophil cytoplasmic antibody)-associated vasculitides. ANCAs are found in patients with small vessel vasculitides, like Wegener's granulomatosis (WG), Microscopic polyangitis (MPA) and Churg Strauss syndrome (CSS). However, cANCA have been found only in 40% and pANCA only in 50% of MPA-patients. In CSS-patients, cANCA as well as pANCA were detectable only in 35 of 100 patients. Hence, the provision of diagnostic markers, particularly for early diagnosis, as well as for the identification of the status of disease and for the stratification of therapy regimen is still a challenge in vasculitis. This is particularly true with large vessel vasculitis, as detailed below.
An overview on polymyalgia rheumatica and giant-cell disease has been given by Salvarani, C. et al., Lancet 2008, 372: 234-245. Giant-cell arteritis (GCA) (also known as Morbus Horton or Arteriitis cranialis) is the main primary systemic vasculitis with a prevalence of 1:500 to 1:1000 in over 50 years old persons in Germany, affecting three times more women than men. GCA affects large and medium-sized vessels whereby inflammation occur mainly in the branches of the A. carotis externa. Intracranial vessels are seldom involved. Thirty to sixty percent of patients with GCA are concomitantly affected with polymyalgia rheumatica (PMR). Both, aetiology and pathogenesis of GCA are presently unknown. Viral infections (with Parainfluenza virus type 1 or Parvovirus B19) and infection with Mycoplasma pneumoniae have been discussed as triggering events for manifestation of GCA.
Histological findings include granulomatous panarteritis of medium- and large-sized arteries with giant-cells (of Langerhans and of foreign body type), infiltration of lymphomononuclear cells (mainly of CD4+ T-cells and macrophages) and stenosed vessel lumen due to proliferation of the intima. Since clonal T-cell expansion is a frequent finding, reaction to a specific antigen is likely.
A cardinal symptom of GCA is headache, occurring mainly unilaterally and localized frontotemporally. The most severe complication occurring in up to ⅓ of patients is blindness due to inflammation of ciliar arteries leading to anterior ischaemic opticus neuropathy. Since this kind of damage to the opticus nerve is nearly irreversible, immediate onset of therapy with cortisone is mandatory when GCA is suspected.
In 10 to 20 percent of patients with GCA only large vessels are affected instead of the temporal arteries and blindness is unlikely. However, thoracic aortitis is often causative of aortic aneurysms and dissections.
Often association of GCA with PMR is found, leading to symmetric myalgia in shoulder, pelvic and neck musculature. Diagnosis of PMR is done by combining clinical symptoms, excluding other diseases and by monitoring the response to glucocorticoids. Pathological findings are much less prominent than in GCA and include a mild synovitis characterized by a predominance of macrophages and CD4+ T-lymphocytes in synovial membranes of involved joints. Until now, analyzing a biopsy of the temporal arteries remains the gold standard in diagnosing GCA, despite two studies drawn up showing a sensitivity up to 90% in diagnosing GCA with high resolution color duplex sonography (used to demonstrate possible vascular wall edema) and with gadolinium-based high-resolution 1.5 or 3 Tesla magnet resonance tomography.
Takayasu's arteritis also known as “aortic arch syndrome” is related to GCA. It is characterized by large vessel granulomatous vasculitis with massive intimal fibrosis and stenosed vessel lumen due to massive intimal fibrosis.
Since complete remission is achievable in case of early diagnosis, there is need for diagnostic markers of vasculitis, in particular, of markers allowing early diagnosis of said diseases, especially for large vessel vasculitis, like GCA, PMR and Takayasu's arteritis.
Up to now no specific diagnostic marker has been established although genetic association of GCA with HLA-DRB1*04 alleles have been described. In patients with PMR the strength of association with HLA-DRB1 varies between different populations. Subjects with variations in HLA-DR*04 alleles are at higher risk of developing GCA and PMR, but analyzing the HLA-DRB1*04 alleles is not suited as a diagnostic test in an individual (Dejaco, C. et al., Akt Rheumatol, 2009, 34, 180-184).
Autoantibodies associated with rheumatoid arthritis (RA) are known (WO 2010/075249). Moreover, autoantibodies against ferritin heavy chain have been detected in patients with rheumatoid arthritis indicating the severity of joint damage (Mewar, D. et al., Arthritis and Rheumatism, Vol. 52, No. 12, 2005, 3868-3872).
In view of the above, there is an ongoing need for providing a diagnostic tool and method allowing diagnosis and assessing the risk of developing vasculitis, in particular, large vessel vasculitis, like GCA, PMR and Takayasu's arteritis, as well as for providing a tool and method for therapy control of vasculitis, in particular large vessel vasculitis, like GCA, PMR and Takayasu's arteritis.